Sustained NF-κB activation produces a short-term cell proliferation block in conjunction with repressing effectors of cell cycle progression controlled by E2F or FoxM1

✍ Scribed by Marianna Penzo; Paul E. Massa; Eleonora Olivotto; Francesca Bianchi; Rosa Maria Borzi; Adedayo Hanidu; Xiang Li; Jun Li; Kenneth B. Marcu

• Publisher: John Wiley and Sons
• Year: 2009
• Tongue: English
• Weight: 483 KB
• Volume: 218
• Category: Article
• ISSN: 0021-9541
• DOI: 10.1002/jcp.21596

✦ Synopsis

Abstract

NF‐κB transcription factors induce a host of genes involved in pro‐inflammatory/stress‐like responses; but the collateral effects and consequences of sustained NF‐κB activation on other cellular gene expression programming remain less well understood. Here enforced expression of a constitutively active IKKβ T‐loop mutant (IKKβca) drove murine fibroblasts into transient growth arrest that subsided within 2–3 weeks of continuous culture. Proliferation arrest was associated with a G1/S phase block in immortalized and primary early passage MEFs. Molecular analysis in immortalized MEFs revealed that inhibition of cell proliferation in the initial 1–2 weeks after their IKKβca retroviral infection was linked to the transient, concerted repression of essential cell cycle effectors that are known targets of either E2F or FoxM1. Co‐expression of a phosphorylation resistant IκBα super repressor and IKKβca abrogated growth arrest and cell cycle effector repression, thereby linking IKKβca's effects to canonical NF‐κB activation. Transient growth arrest of IKKβca cells was associated with enhanced p21 (cyclin‐dependent kinase inhibitor 1A) protein expression, due in part to transcriptional activation by NF‐κB and also likely due to strong repression of Skp2 and Csk1, both of which are FoxM1 direct targets mediating proteasomal dependent p21 turnover. Ablation of p21 in immortalized MEFs reduced their IKKβca mediated growth suppression. Moreover, trichostatin A inhibition of HDACs alleviated the repression of E2F and FoxM1 targets induced by IKKβca, suggesting chromatin mediated gene silencing in IKKβca's short term repressive effects on E2F and FoxM1 target gene expression. J. Cell. Physiol. 218: 215–227, 2009. © 2008 Wiley‐Liss, Inc.